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Inhibition of Hepatocyte DNA Synthesis by Transforming Growth Factor ß₁ and Cyclic AMP: Effect Immediately before the G₁/S Border¹

Department of Pharmacology, Faculty of Medicine, University of Oslo, Oslo, Norway

Previous studies have shown that both transforming growth factor ß (TGF-ß) and cyclic AMP (cAMP) inhibit hepatocyte DNA synthesis. While cAMP (in addition to being stimulatory in G₀/early G₁) exerts its inhibition on hepatocytes late in G₁, the point where TGF-ß inhibits has not been precisely defined. We have now examined further the inhibitory effects of cAMP and TGF-ß₁ on DNA synthesis in primary rat hepatocyte cultures and, in particular, tried to determine where in the prereplicative period the cells are sensitive to these agents. Although a transient exposure to TGF-ß₁ (but not glucagon) during the first hours of the cell culturing led to inhibition of DNA synthesis, the cells were more sensitive at a point late in G₁, where they also were inhibited by cAMP. Thus, exposure to TGF-ß₁, glucagon, or the cAMP analogue 8-chlorophenylthio-cAMP at a time when there was a continuous recruitment of cells to S phase strongly decreased the rate of S-phase entry. For both TGF-ß₁ and cAMP the inhibition was established within 1–2 h, the lag time being indistinguishable for the two agents. No evidence was found for a synergism between TGF-ß₁ and cAMP. Treatment with TGF-ß₁ did not detectably alter basal or glucagon-stimulated cAMP concentrations. The results suggest that in hepatocytes there is a process immediately before the G₁/S border which is sensitive to both TGF-ß₁ and cAMP and which appears to represent a major point of inhibition.

¹ Supported in part by grants from the Norwegian Council for Science and the Humanities and the Nordic Insulin Fund.

² G. H. T. is a Research Fellow of the Norwegian Cancer Society. To whom requests for reprints should be addressed, at Department of Pharmacology, Faculty of Medicine, University of Oslo, P. O. Box 1057 Blindern, N-0316 Oslo 3, Norway.

³ Present address: Laboratory of Experimental Carcinogenesis, Division of Cancer Etiology, National Cancer Institute, Bethesda, MD 20892.

Received 1/21/92. Accepted 4/23/92.

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